Gonadotropin-releasing hormone (GnRH) is the primary neural signal regulating reproduction in mammals. Insulin signaling within the hypothalamus is necessary for normal reproductive function in vivo in mice and insulin increases GnRH gene expression in vitro. IGF-1 receptor shares signaling pathways with the insulin receptor, increases GnRH expression in vitro, and in vivo plays a permissive role in puberty onset. Preliminary data indicate that the transcription factor Egr-1 binds the GnRH promoter in response to insulin. IGF-1 increases c-fos mRNA in vitro whereas insulin does not. In fasted transgenic mice, insulin treatment increases mouse GnRH promoter activity. The overall goal of this project is to examine the regulation of GnRH neuron function in vitro and in vivo by insulin and IGF-1 signaling pathways. The regulatory regions and transcription factors mediating the insulin and IGF-1 stimulation of GnRH transcription in vitro will be delineated. Insulin and IGF-1 effects on GnRH secretion will be examined. The in vivo role of insulin and IGF-1 to GnRH neuron function will be examined using the CRE-lox system to generate GnRH specific insulin or IGF-1 receptor knockout mice. To examine the role of Egr-1 to GnRH neuron function in vivo, GnRH specific Egr-1 knockout mice will be generated. This project will be conducted by Dr. Sara DiVall under the guidance of Drs. Andrew Wolfe and Sally Radovick in the Division of Pediatric Endocrinology at Johns Hopkins University. Dr. DiVall, a Pediatric Endocrinologist, is dedicated to a career in academia using basic and translational research to study pubertal and reproductive disorders. Drs. Wolfe and Radovick have exceptional research careers using molecular endocrinology and in vivo mouse models to study the regulation of GnRH gene expression and have the necessary expertise to provide Dr. DiVall with the training to become an independent researcher. The available resources and the collaborating research faculty within the divisions of Pediatric Endocrinology, Pediatric Metabolism, and the Chicago-Baltimore Cooperative Center for Reproductive Research provide a rich learning environment. Both caloric deficiency and excess are associated with reproductive dysfunction in humans. These studies will provide insight into how the brain's control of reproduction is affected by the nutrition dependent hormones insulin and insulin-like growth factor-1.